Myxoid Adrenocortical Carcinoma
A Clinicopathologic and Immunohistochemical Study of 7 Cases, Including 1 Case With Lipomatous Metaplasia
Annikka Weissferdt, MD, FRCPath,1 Alexandria Phan, MD,2 Saul Suster, MD,3 and Cesar A. Moran, MD1
Key Words: Adrenocortical carcinoma; Myxoid change; Immunohistochemistry; Endocrine tumor
DOI: 10.1309/AJCPCDZLC13RSXRZ
Abstract
Adrenocortical carcinomas (ACCs) with myxoid features are rare neoplasms. We identified 7 cases of myxoid ACC and studied the clinicopathologic and immunohistochemical features of these neoplasms. The patients were 5 men and 2 women with a mean age of 45 years. Histologically, the tumors contained alcian blue-positive myxoid areas ranging from 10% to 50% of the tissue examined. One case showed lipomatous metaplasia. Areas of conventional ACC were present in all cases. Immunohistochemically, the tumors were positive for steroid receptor cofactor 1, inhibin, melan A, calretinin, and synaptophysin but negative for high-molecular-weight cytokeratin, CAM5.2, and Pax8. Clinical follow-up information for 4 patients demonstrated that all patients had died of their disease 11 to 69 months after diagnosis. Myxoid ACCs are rare tumors that expand the differential diagnosis of myxoid neoplasms involving the retroperitoneum. Contrary to previous reports proposing that the biologic behavior is similar to conventional ACC, our series seems to indicate that myxoid morphology is associated with more aggressive behavior.
Adrenocortical carcinomas (ACCs) are rare malignant neoplasms of the adrenal cortex with an incidence of 0.7 to 2 cases per million population.1 These tumors most often affect patients during the fifth decade of life but are also not uncom- mon in children. Females are more commonly affected than males. In addition to different architectural patterns in conven- tional ACC, including diffuse, trabecular, nested, or alveolar patterns, several distinct tumor subtypes have been described, including oncocytic, sarcomatoid, and myxoid variants. To date, fewer than 35 myxoid ACCs have been described in the English literature.2-11 This variant is characterized by tumor cells arranged in cords, clusters, or pseudoglandular structures embedded in a prominent myxoid stromal background. These myxoid areas may be focal or involve the entire tumor tissue. The clinical, immunohistochemical, and ultrastructural find- ings are thought to be similar to those of conventional ACC.7,8 Another unusual feature described in a single case of myxoid ACC is the presence of lipomatous metaplasia,5 a process previously thought to be associated only with benign adreno- cortical lesions. In this study, we report the clinicopathologic and immunohistochemical characteristics of 7 myxoid ACCs and detail the spectrum of morphologic features that these tumors may show.
Materials and Methods
During a review of 77 cases of ACC, 7 cases (9%) with myxoid features were identified from the surgical pathology files of the MD Anderson Cancer Center (Houston, TX) and the Medical College of Wisconsin, Milwaukee. H&E-stained sections from adrenalectomy specimens were available for
review in each case. All tumors were confirmed as ACC according to the Weiss criteria.12 Representative paraffin blocks were available for histochemical and immunohisto- chemical studies. Paraffin-embedded tissue sections of 2 cases were stained with alcian blue (pH 2.5), periodic acid-Schiff (PAS), and mucicarmine stains. Deparaffinized tissue sections of 3 cases were incubated with antibodies directed against high-molecular-weight cytokeratin (1:50; Dako, Carpinteria, CA), CAM5.2 (1:50; BD Biosciences, San Jose, CA), inhibin (1:50; AbD Serotec, Raleigh, NC), melan A (1:25; Novocas- tra, Buffalo Grove, IL), chromogranin (1:100; Dako), synap- tophysin (1:200; Dako), calretinin (1:40; Invitrogen, Carlsbad, CA), steroid receptor cofactor 1 (1:100; Cell Signaling, Dan- vers, MA), Pax8 (1:100; Protein Tech, Chicago, IL), and Ki67 (1:200; Dako) using the polymeric biotin-free horseradish peroxidase method. Appropriate negative and positive con- trols were run for all antibodies tested. Clinical and follow-up information were obtained from the patients’ medical records or from referral information where available.
Results
Clinical Features
The main clinical features are summarized in ITable 11. The patients were 5 men and 2 women aged 19 to 66 years (mean, 45 years). Two patients presented with symptoms related to hormone secretion, more specifically Cushing syn- drome. Abdominal pain led the other patients to seek medical attention. The right adrenal gland was affected in 5 cases and the left adrenal gland in 2. None of the patients had a prior his- tory of malignancy. Preoperative pathologic staging accord- ing to the seventh edition of the American Joint Committee on Cancer staging manual13 showed that 1 patient had T2 disease (tumor >5 cm, no extra-adrenal invasion) and 2 patients had T3 disease (tumor of any size with local invasion, not invad- ing adjacent organs); for the rest of the patients, no staging
information was available. Treatment consisted of adrenalec- tomy in all cases. Adjuvant chemotherapy with mitotane was administered in at least 2 cases (Table 1).
Gross Features
The lesions were described as variably encapsulated tumors with a lobulated architecture and a variably gelati- nous translucent or fleshy tan-yellow cut surface. The tumors ranged in size from 6 to 14.5 cm. Weight information was recorded for only 1 case (516 g). Areas of necrosis and hemorrhage were a frequent finding. Yellow-golden strips of normal adrenal gland tissue were identified macroscopically in 3 cases.
Histologic Features
The histologic features were similar in all cases. At low magnification, all tumors exhibited either diffuse or lobulated growth patterns IImage 1Al and IImage 1BI. At higher magni- fication, the tumor cells were arranged in trabeculae, clusters, or cords floating in a prominent myxoid stromal background IImage 1C, IImage 1DI, and IImage 1El. In several cases, a pseudoglandular or microcystic pattern was apparent IImage 1FI. Two cases showed a nodular or club-shaped arrangement of cells with hypocellular centers and tumor cells radiating outward, forming more cellular peripheral outlines IImage 2Al. The individual tumor cells were either small with angu- lated and hyperchromatic nuclei and small or inconspicuous nucleoli or large and pleomorphic with polygonal shape, eosinophilic cytoplasm, vesicular nuclei, and prominent nucleoli IImage 2BI and IImage 2CI. The myxoid stroma was characterized by pools, lakes, or microcysts of loose mucoid material. In 2 cases, this stroma adopted a more dense appear- ance reminiscent of chondroid matrix material IImage 2DI. This myxoid change represented 10% to 50% of the tumor volume submitted in each case. The mitotic count ranged from 2 to more than 20 mitoses per 10 high-power fields. Atypical mitotic forms were not identified in any case. Tumor necrosis was present in 3 cases, ranging from 10% to 30%. Areas of
| Case No. | Sex | Age, y | Functional State | Laterality | % of Myxoid Change | Tumor Stageª | Metastasis/Recurrence | Treatment | Follow-up, mo |
|---|---|---|---|---|---|---|---|---|---|
| 1 | F | 58 | Functional | Right | 50 | T2 | Recurrence with invasion of kidney, liver, and retroperitoneum | Surgery/CT | D/69 |
| 2 | M | 51 | Functional | Right | 30 | T3 | Metastasis to bone | Surgery/CT | D/11 |
| 3 | M | 66 | NK | Left | 10 | T3 | NK | Surgery/NK | D/12 |
| 4 | F | 19 | NK | Right | 40 | NK | Metastasis to liver | Surgery/NK | D/11 |
| 5 | M | 45 | NK | Right | 40 | NK | NK | Surgery/NK | NK |
| 6 | M | 29 | NK | Left | 30 | NK | NK | Surgery/NK | NK |
| 7 | M | 47 | NK | Right | 10 | NK | NK | Surgery/NK | NK |
CT, chemotherapy (mitotane); D, deceased; NK, not known.
a According to the seventh edition of American Joint Committee on Cancer staging manual.
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5
more conventional ACC characterized by eosinophilic or lipid-rich clear cells arranged in diffuse, trabecular, or nested growth patterns were present in all cases IImage 2EI. A small rim of normal adrenal gland was present in 3 cases. Another distinct morphologic change observed in a single case were areas of mature adipocytes intimately admixed with the tumor cells Image 2FI. The tumor cells surrounding the adipocytic component had prominent clear vesicular cytoplasm mimick- ing immature adipocytes or lipoblasts. The pathologic charac- teristics are summarized in ITable 21.
Immunohistochemical Features
Histochemical studies were performed in 2 cases and showed the myxoid material to be positive for alcian blue and negative for PAS and mucicarmine stains IImage 3Al and IImage 3BI. Immunohistochemical studies were performed in 3 cases. The tumor cells of all 3 cases were diffusely posi- tive for steroid receptor cofactor 1, inhibin, calretinin, melan A, and synaptophysin IImage 3CI, Image 3DI, IImage 3El, and IImage 3FI. Negative markers included high-molecular- weight cytokeratin, CAM5.2, chromogranin, and Pax8. The Ki67 proliferative index ranged from less than 5% to 10%.
Clinical Follow-up
Follow-up information available for 4 patients demon- strated that all patients succumbed to their disease 11 to 69 months after diagnosis; in 3 patients, local tumor recurrence or distant metastasis was recorded. Three patients were lost to follow-up (Table 1).
Discussion
Myxoid ACCs are rare tumors of the adrenal cortex, and to date fewer than 35 myxoid ACCs have been described in the English literature.2-11 In summary, all these reports state similar clinical characteristics as for conventional ACC. Patients are usually in the fifth decade of life at presenta- tion, but sex distribution in myxoid tumors is nearly equal. Presenting symptoms may be hormone related and most often represented by evidence of glucocorticoid excess. Tumor size
and weight are also comparable to conventional ACC. The characteristic morphologic appearance is a variable propor- tion of myxoid stroma, which can range from 10% to 60% of the total tumor volume. This myxoid material is typically alcian blue positive and negative for PAS or mucicarmine stains. Tumor cells are arranged in cords, trabeculae, clusters, or pseudoglandular structures, often floating in pools or lakes of myxoid material. The nonmyxoid areas are often composed of conventional ACC. The immunohistochemical phenotype is identical to conventional ACC, which is typically posi- tive for inhibin, melan A, synaptophysin, and vimentin and variably reactive for cytokeratin. Ultrastructurally, the tumor cells contain rough endoplasmic reticulum, mitochondria with tubulovesicular cristae, and lipid droplets in the absence of neurosecretory granules. More recently, a Chinese study investigated a series of myxoid adrenocortical neoplasms on a molecular level and concluded that epidermal growth factor receptor (EGFR) protein expression was a common finding in these tumors, but EGFR gene mutation was universally absent.10 The biologic behavior of myxoid ACC is thought to be similarly aggressive as for conventional ACC.7,8
In the cases described herein, some features in terms of clinical presentation and morphologic and immunohistochem- ical findings strongly resemble those described previously. However, one important issue to highlight is that all patients for whom follow-up information was available died of their disease 11 to 69 months after diagnosis, once again emphasiz- ing the aggressive nature of these tumors. Our findings seem to suggest that myxoid morphology may be associated with an even worse prognosis than conventional ACC. It is important to prospectively analyze these tumors in a large cohort to fully determine their clinical behavior.
The etiology and significance of myxoid change in adre- nocortical tumors have long been a matter of debate. In one of the earliest reports on myxoid ACC, Forsthoefel3 in 1994 speculated that myxoid change was a degenerative phenom- enon or the result of production by stromal fibroblasts and was negatively correlated with functional status. Other proposals included the belief that the myxoid matrix was produced by the cells of the adrenal cortex, but no intracellular myxoid
ITable 21 Pathologic Features of 7 Patients With Myxoid Adrenocortical Carcinoma
| Case No. | Myxoid Area, % | Mitoses, per 10 hpf | Necrosis, % | Vascular Invasion | Capsular Invasion |
|---|---|---|---|---|---|
| 1 | 50 | 10 | 0 | Absent | Absent |
| 2 | 30 | >20 | 0 | Absent | Present |
| 3 | 10 | 6 | 10 | Absent | Present |
| 4 | 40 | 3 | 20 | Present | Present |
| 5 | 40 | 2 | 0 | Absent | Absent |
| 6 | 30 | 11 | 30 | Absent | Present |
| 7 | 10 | 2 | 0 | Absent | Absent |
hpf, high-power field.
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material could be demonstrated.14 Although we believe that a degenerative process is the most likely explanation, to date the significance of myxoid change or its mechanism of pro- duction remains speculative, necessitating further studies into this phenomenon.
One additional morphologic change that we were able to appreciate in 1 of our cases was the presence of lipoma- tous metaplasia. Lipomatous change in the adrenal gland mostly has been associated with benign disorders or tumoral conditions15-17 and only once before has been described in a myxoid ACC.5 In our case, areas of mature adipocytes were found dispersed throughout the tumor in a similar pattern to that reported in the previous case. Various hypotheses have been put forward to explain such an occurrence, including the possibility that this represents a reactive process in response to degeneration or a metaplastic process of the neoplastic cells. The latter possibility was favored by Izumi et al5 in their description of lipomatous metaplasia in a myxoid ACC. The authors argued that their case contained cells at various stages of metaplasia with increasing lipid accumulation in tumor cells, leading to a prominent vesicular or vacuolated cytoplasm and eventually resembling mature adipocytes. The fact that a spectrum of such cells was also seen in one of our cases seems to support the idea of a metaplastic process.
The importance of recognizing myxoid change in ACC is that it expands the spectrum of tumors that can contain myx- oid material in the retroperitoneum. The differential diagnosis of tumors that can display myxoid change in this location is already wide and includes myxoma, liposarcoma, malignant fibrous histiocytoma, nerve sheath tumors, smooth muscle tumors, carcinomas, chordoma, extraskeletal myxoid chon- drosarcoma, and gastrointestinal stromal tumor. A combina- tion of the clinical parameters, thorough radiologic correlation to determine the exact location of the tumor, careful histologic assessment of the tumor morphology, and an immunohisto- chemical panel to include markers associated with adreno- cortical differentiation should help to establish the diagnosis.
In summary, we have presented 7 cases of myxoid ACC and have discussed their clinicopathologic and immunohisto- chemical characteristics. Myxoid ACCs are rare tumors that need to be included in the differential diagnosis of myxoid neoplasms that may arise in the retroperitoneal area. As with other benign conditions of the adrenocortical cortex, lipo- matous change can also be associated with malignant adre- nocortical tumors. The early mortality in our cases appears to suggest that myxoid ACCs have an even more aggressive biologic behavior than conventional ACCs.
From the ‘Department of Pathology and 2Department of GI Medical Oncology, MD Anderson Cancer Center, Houston, TX, and 3Department of Pathology, Medical College of Wisconsin, Milwaukee.
Address reprint requests to Dr Weissferdt: Dept of Pathology, MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030; e-mail: aweissferdt@doctors.org.uk.
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